Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice

Int Immunol. 2007 Mar;19(3):267-76. doi: 10.1093/intimm/dxl143. Epub 2007 Jan 17.

Abstract

Previous studies on c-Abl-deficient mice have shown high post-natal mortality and lymphopenia. However, the mechanisms by which c-Abl may influence B lymphopoiesis remain obscure. In this study, we analyzed B cell sub-populations at various differentiation stages in the bone marrow (BM) of c-Abl-deficient mice. Phenotypic analyses revealed that c-Abl(-/-) pro-B cells were reduced to half of normal incidence and absolute number, while pre-B cells showed an even greater reduction. Both c-Abl(-/-) pro-B and pre-B cell populations showed considerably elevated apoptosis ex vivo and in short-term culture but their cell cycle progression was not impaired. In contrast, apoptosis of immature IgM(+)IgD(-) B lymphocytes remained at normal control levels. Inhibition of c-Abl activity by STI571 in normal BM cultures significantly increased apoptosis in B cell precursors while the survival of immature B cells was not affected. To determine whether c-Abl deficiency affects Ig heavy-chain rearrangement, we found that the frequency of V(D)J recombination was markedly reduced by 15-fold in c-Abl(-/-) pro-B cells compared with the control values. However, no perturbation in the levels of signal-end recombination intermediates was found. Taken together, we propose that c-Abl mediates a stage-specific anti-apoptotic response in precursor B cells and is required for efficient V(D)J recombination during B cell development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / genetics
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism*
  • Cell Cycle / genetics
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cells, Cultured
  • Gene Rearrangement, B-Lymphocyte*
  • Immunoglobulin Heavy Chains / genetics
  • Lymphopoiesis* / genetics
  • Mice
  • Mice, Knockout
  • Phenotype
  • Proto-Oncogene Proteins c-abl / deficiency*
  • Proto-Oncogene Proteins c-abl / genetics
  • Recombination, Genetic*
  • VDJ Recombinases / metabolism

Substances

  • Immunoglobulin Heavy Chains
  • Proto-Oncogene Proteins c-abl
  • VDJ Recombinases